Resibufogenin inhibits ovarian clear cell carcinoma (OCCC) growth in vivo, and migration of OCCC cells in vitro, by down-regulating the PI3K/AKT and actin cytoskeleton signaling pathways

Patients diagnosed with ovarian clear cell carcinoma (OCCC), a rare histologic subtype of ovarian Cancer, often experience poor prognosis owing to the chemoresistance of their disease. Thus, there is an urgent need to identify new therapeutic options for these patients. A drug screen of 172 traditional Chinese herbs identified resibufogenin as a compound that inhibited the growth of cultured OCCC cells. Resibufogenin, a bioactive compound originally isolated from toad venom, is used in traditional Chinese medicine to treat several malignancies. The current study examined the impact of resibufogenin treatment on proliferation, migration, and invasion of ES-2 and TOV-21G OCCC cells in vitro. Flow cytometric analyses were employed to determine if resibufogenin affects Apoptosis in OCCC cells. Additionally, the ability of resibufogenin to inhibit tumor growth in vivo was evaluated in murine xenograft models. RNA sequencing, quantitative polymerase chain reactions (qPCR), immunohistochemical assays, and western blotting were used to identify and verify cellular pathways potentially targeted by resibufogenin. Resibufogenin inhibited proliferation, migration, and invasion of OCCC cells, and induced Apoptosis in them. Resibufogenin also suppressed the growth of xenograft tumors, which consequently showed lower Ki-67 and higher terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) expression. We observed down-regulation of (a) PI3K and Akt in the PI3K/Akt signaling pathway, and (b) MDM2 and Myosin in the actin Cytoskeleton pathway upon resibufogenin treatment. Thus, resibufogenin inhibits growth and migration of OCCC cells in vitro and suppresses OCCC growth in vivo through the PI3K/Akt and actin Cytoskeleton signaling pathways.